tbuckley/cabot-search huggingface dataset:
A phase I clinical trial of stereotactic body radiotherapy with atezolizumab and bevacizumab in advanced hepatocellular carcinoma.
Authors: Timothy J Brown, Andy J Minn, Erica L. Carpenter, Edgar Ben-Josef, Thomas Benjamin Karasic
Journal: Journal of Clinical Oncology (2023)

TPS626 Background: Systemic therapy with atezolizumab and bevacizumab (atezo/bev) has improved outcomes for advanced HCC, but results in objective responses in fewer than 30% of patients. Stereotactic body radiotherapy (SBRT) is currently used for small HCC tumors that do not require systemic therapy but has also been shown in a number of clinical trials of other solid tumors to enhance the anti-cancer immune response. Of particular interest, our prior experience with SBRT in a 17Gy fraction has demonstrated the ability to restore sensitivity to immunotherapy in advanced solid tumors, even those previously refractory to immunotherapy. We hypothesize that repeated high dose fractions of radiation will act as an immune booster and will improve on outcomes of patients with advanced HCC. Since the combination of SBRT and atezo/bev has not yet been tested prospectively in patients with HCC, and because bevacizumab is a known radiosensitizer, we are conducting a phase I trial to evaluate the safety of repeated SBRT doses. Methods: This is a single-site phase I clinical trial utilizing a Rolling 6 design to determine the safety of 1, 2, or 3 doses of SBRT fractions in combination with atezo/bev. Up to 18 total patients will be enrolled (n=6 per cohort). Patients must be naïve to systemic therapy with Child-Pugh A or B liver function, at least one lesion amenable to radiation, and a measurable lesion that will not receive radiation. Patients with uncontrolled ascites or hepatic encephalopathy are excluded. Atezo/bev is administered at the standard doses every 21 days. SBRT will start 1 week after the first infusion of this combination. Patients will receive 1, 2, or 3 17Gy fractions of SBRT at 4-week intervals (cohorts 2 and 3 only). Patients will undergo serial collections of circulating cell-free DNA (ccfDNA), methylated DNA, and peripheral blood mononuclear cells to investigate the application of these markers as a predictor of response. Following completion of SBRT, patients will continue with atezo/bev until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is the proportion of patients experiencing dose-limiting toxicities (grade 3 or higher radiation-related toxicities graded by the Common Terminology Criteria for Adverse Events, Version 5). Secondary endpoints are overall survival, progression-free survival, objective response rate, duration of response, and toxicity rates. Enrollment began 9/2022 and complete accrual is expected by June 2024. NCT05488522. Clinical trial information: NCT05488522 .
Impact of dose adjustment of fluoropyrimidines on toxicity in patients with DPD-deficient colorectal cancer: A single-center experience.
Authors: Daniel Martinez-Perez, Ismael Ghanem, Rocio Rosas-Alonso, Pedro Arias, Sonia Rodriguez-Novoa, Alberto Borobia, David Viñal, Iciar Ruiz-Gutierrez, Diego Jiménez-Bou, Nuria Rodriguez Salas, Jaime Feliu Batlle
Journal: Journal of Clinical Oncology (2023)

94 Background: Fluoropyrimidines (FPs) are the chemotherapy backbone for most patients with CRC. FPs are metabolized by dihydropyrimidine dehydrogenase (DPD). Current guidelines recommend measuring DPD activity before chemotherapy administration to adjust the initial dose and thus prevent high-grade toxicity. However, the clinical impact of this strategy is still understudied. We aim to study the efficacy and toxicity of FPs dose modifications according to DPD activity in patients with CRC. Methods: We retrospectively identified all the CRC cancer patients treated with FPs between January 2017 and July 2021 and with DPD activity assessment at Hospital Universitario La Paz, Madrid, Spain. Clinical characteristics and tolerability were collected. Two cohorts were stablished according to its DPD activity, patients with a normal DPD metabolism (DPD wild-type patients) and patients with a diminished metabolism of FPs (DPD deficient patients). Results: A total of 249 CRC patients were included in this study. Sixteen patients (6,4%) were DPD deficient, and 15 of them (94%) received initially 50% of the recommended standard dosing of FPs (increasing to 75% in following cycles if well tolerated) according to guidelines. Forty percent of non-DPD deficiency started FPs at 75% of the standard initial dose due to frailty. Two toxic deaths were observed in the DPD-wild-type cohort, none in the DPD deficient cohort. Clinico-pathological characteristics of patients and their toxicity according to each cohort are depicted in the table. No significant differences in G3/4 toxicity between both groups (40% and 37% in the DPD-wild-type and DPD-deficient cohort, respectively). Diarrhea G3/4 was numerically more present in the DPD-deficient group (25% vs 12%, respectively). Conclusions: Overall, DPD genotype-guided FP treatment in DPD deficient patients with CRC may prevent high-grade toxicity. Diarrhea might still be higher in this group despite dose modifications, so careful surveillance and early treatment should be considered in these patients. [Table: see text]
Updated analysis: Effect of biweekly dosing schedule of trifluridine-tipiracil (TAS-102) on rates of myelosuppression and maintenance of therapeutic efficacy in patients (pts) with previously treated metastatic colorectal cancer (mCRC).
Authors: Christopher G Cann, Michael Brian LaPelusa, Sarah Cimino, Brian Grieb, Kristen Keon Ciombor, Rajiv Agarwal, Satya Das, Laura Williams Goff, Dana Backlund Cardin, Shemeka Davis, Jordan Berlin, Cathy Eng
Journal: Journal of Clinical Oncology (2023)

95 Background: For surgically unresectable metastatic colorectal cancer pts, a continuum of treatment is required to improve the OS of our pts. Oral trifluridine-tipiracil (TAS-102) is FDA approved in refractory mCRC per the RECOURSE trial. As per the FDA insert, the recommended dose is 35 mg/m 2 twice daily (maximum = 80 mg/day) on Days 1-5 and Days 8-12 of 28-day cycles commonly resulting in Grade 3-4 neutropenia (38%), dose delays (53%), dose reductions (14%) and requiring G-CSF support (9%). To maintain efficacy and to potentially reduce toxicity, we analyzed an alternative biweekly dosing (Days 1-5 and Days 15-19 q28 days). Methods: A retrospective analysis was completed (2019-2022) at Vanderbilt-Ingram Cancer Center in pts with refractory mCRC and appendiceal cancer (CA) who completed ≥ 12 days of TAS-102 therapy and underwent surveillance imaging every 8-12 weeks. Patient data was assessed for ECOG performance status (PS), prior lines of therapy, the use of bevacizumab and CTCAE grade of treatment-related myelotoxicity. Evaluation of progression-free survival (PFS) was completed in mCRC pts. Results: Forty-three patients met the inclusion criteria, with a mCRC:appendiceal CA ratio of 39:4. The median age = 50 y/o (range 30-80); male:female 23:20; median ECOG PS = 1; median number of prior therapies = 3; and median duration of therapy = 97 days (range: 12-396). Associated grade 3/4 hematologic toxicities included: Neutropenia 39% [Grade 3 (12.2%), Grade 4 (2.4%)]; anemia 36.5% [Grade 3 (12.2%)]. No pts required G-CSF. No incidences of neutropenic fever were reported. Five pts (11.6%) required a dose delay and 3 pts (7%) required a dose reduction due to myelosuppression. In mCRC pts, the median PFS was 2.53 months. To date, 6 pts remain on treatment (range: 97-331). Conclusions: In our updated analysis, biweekly dosing of TAS-102 (35 mg/m 2 twice daily; Days 1-5 and Days 15-19 of 28-day cycles) for pts with refractory mCRC and appendiceal CA demonstrated tolerable myelosuppression, while preserving PFS in pts with mCRC. With an improved toxicity profile, this alternative TAS -102 dosing schedule may potentially broaden utilization of TAS-102 in patients with borderline PS and may be a more favorable option for future combination studies. Additional prospective data are needed to validate these findings. To our knowledge, this remains the first analysis of biweekly TAS-102 in a US patient population.
LEANOX: Lean body mass normalization of oxaliplatin-based chemotherapy for patients with stage III colon cancer treated in adjuvant setting: Impact on oxaliplatin-induced sensitive neurotoxicity—A multicenter phase II randomized trial.
Authors: Eric Assenat, Meher BEN Abdelghani, Maeva Monnier, Herve Perrier, Faiza Khemissa, Romain Desgrippes, Marie-Pierre Galais, Yves Rinaldi, Come Lepage, Raphael Tetreau, Pierre Senesse
Journal: Journal of Clinical Oncology (2023)

92 Background: Adjuvant chemotherapy is the current worldwide standard of care for stage III colorectal cancer (CRC) but it leads to significant neurotoxicity. We have shown in 2 cohorts of CRC patients treated with Oxaliplatin (Ox) that Ox-due neuropathy occurred in patients receiving an excess of 3.09 mg Ox/ kg Lean Body Mass (LBM). The aim of this trial was to determine whether the Ox dose adaptation based on the LBM index can reduce neurotoxicity, in patients treated for a stage III CRC. Methods: LEANOX is a randomized phase II multicentre study in patients eligible for an Ox regimen as adjuvant chemotherapy for CRC. Patients without sarcopenia (LBM index &lt;3.09mg/kg, group 1) received a dosage of Ox according to Body Surface Area (BSA) (85 mg/m²).Patients with sarcopenia (LBM index ≥3.09mg/kg) were randomized in 2 groups, group 2: dosage of Ox according to BSA (similar to group 1) and group 3: a dosage of Ox according to LBM (3.09 mg Ox/ kg LBM). Randomization (1:1) was stratified by center, age and weight loss. The primary endpoint was the percentage of patients without grade ≥2 neurotoxicity during the first 6 cycles of adjuvant Ox-based chemotherapy. The study required 108 randomized patients (bilateral α=0.05, 80% power) to compare the primary endpoint between groups 2 and 3 with P2=55% and P3=80%. Secondary endpoints included time to onset of grade≥2 chronic cumulative neurotoxicity, duration of the chronic cumulative neurotoxicity, cumulative Ox doses that can be delivered without reaching the dose-limiting chronic neurotoxicity, tolerance, disease free survival, overall survival and quality of life. Results: A total of 160 patients were included in 18 french centers: 33 in group 1, 64 in group 2 and 63 in group 3. Median age was 63 years, 52.5 % male, 89.3 % OMS 0 and tumoral stage was T3 (57.5%), T4 (33.8%), N1 (60.6%) and N2 (38.1%). Grade 3-4 AE events occurred in 58.0% in group 2 and 59.7% in group 3. The percentage of patients without experiencing grade ≥ 2 of neurotoxicity during the first 6 cycles of adjuvant Ox-based chemotherapy was 43.9% in group 2 vs 67.2% in group 3 (p=0.01). Conclusions: We wish to avoid severe adverse reactions to Ox regimen by personalization of cancer chemotherapy. Clinical trial information: NCT03255434 .
A phase1b study of navicixizumab plus FOLFIRI in second-line treatment of patients with metastatic colorectal cancer.
Authors: Kian-Huat Lim, Michael Iglesia, Kerry Culm, Andrew G. Koustenis, Colleen M. Mockbee, Lynn Mathew, Marwan Fakih, Ignacio Garrido-Laguna, John C. Krauss
Journal: Journal of Clinical Oncology (2023)

111 Background: Navicixizumab is an anti-delta-like ligand 4 (DLL4)/vascular endothelial growth factor bispecific antibody which has shown promising preclinical and clinical activity in multiple tumor types. The blockade of DLL4, a transmembrane protein acting as a ligand for Notch receptors 1 and 4, causes tumor differentiation and reduction in cancer stem cells, as well as repolarization of the tumor microenvironment. Methods: We conducted a phase 1b single-arm dose escalation study combining navicixizumab with FOLFIRI or FOLFOX as second line treatment for patients with metastatic colorectal cancer (CRC). Patients were dosed either at 3 or 4 mg/kg intravenously once every 2 weeks (Q2W). The primary endpoint was the maximum tolerated dose of navicixizumab in combination with FOLFOX or FOLFIRI. Results: Between December 2016 and August 2018, 15 patients received navicixizumab plus FOLFIRI. Median patient age was 55 years, and nine of 15 patients were female (60%). Three patients were enrolled in the 3 mg/kg dose-escalation cohort, 2 patients were enrolled in the 4-mg/kg dose-escalation cohort, and 10 patients were enrolled in the 3 mg/kg dose expansion cohort. No DLTs were observed in this study. The median duration of navicixizumab therapy was 127 days. Hypertension was the most frequent all-grade treatment-related adverse event reported (12 of 15 patients, 80%), followed by fatigue (8 of 15 patients, 53.3%). Grade 3 hypertension was reported in 3 patients (20%). Eight of the 15 patients (53.3%) experienced at least one serious adverse event, resulting in discontinuation of study for 6 (40%) patients. One patient had a bowel perforation. One patient (3 mg/kg cohort) experienced a treatment-related grade 5 cardiopulmonary arrest resulting in death. The best overall response was partial response in three patients (20%). Eleven patients (73.3%) had stable disease and one (6.7%) experienced disease progression. Conclusions: This study was stopped early to focus on the development of navicixizumab in ovarian cancer. Although the disease control rate was promising, further evaluation is needed to determine whether navicixizumab delivers efficacy greater than chemotherapy alone and assess tolerability of this regimen. [Table: see text]
The efficacy and safety of neoadjuvant sintilimab combined with chemotherapy in elderly patients with locally advanced esophageal squamous cell carcinoma.
Authors: Huilai Lv, Chao Huang, Jiachen Li, Fan Zhang, Chunyue Gai, Zhao Liu, Shi Xu, Mingbo Wang, Zhenhua Li, Ziqiang Tian
Journal: Journal of Clinical Oncology (2023)

378 Background: Neoadjuvant PD-1 inhibitor combined with chemotherapy has been reported to improve the pathologic response of locally advanced esophageal squamous cell carcinoma (ESCC). However, systematic report of efficacy and safety data in elderly Chinese patients is lacking. This study we report the efficacy and safety outcomes of neoadjuvant sintilimab combined with chemotherapy in elderly patients with locally advanced ESCC. Methods: Elderly patients (70 years or older) with locally advanced ESCC received neoadjuvant sintilimab combined with albumin-bound paclitaxel and nedaplatin in our institution between July 2019 and September 2022 were reviewed. Efficacy including pathologic response, short-term survival outcomes, and safety profile retrospectively were evaluated. Results: Thirty-one eligible patients were included in the analysis, with median age 72 years (range 70-78 years), male 18 (58.1%), Upper/middle/lower tumors 2(6.5%)/15(48.4%) /14(45.2%), ECOG PS 0/1-2 15 (48.4%)/16 (51.6%), clinical stage II/III 14 (45.2%)/17 (54.8%). The median number of neoadjuvant cycles was 3 (range 2-4). All 31 patients achieved R0 resection. Postoperative pathology showed pCR rate was 45.2% (95CI 27.3%-64.0%), MPR rate was 58.1% (95CI 39.1%-75.5%), tumor down-staging rate was 90.3% (95CI 74.2%-98.0%). With a median follow-up of 15.9 months (range 3.0-32.3), 1 (4.2%) patient had disease recurrence and died. The median DFS and median OS had not been reached yet, 2-year DFS rate was 95.0% (95%CI 85.9%-100.0%). Grade 3-4 Surgical complications occurred in 1 (4.2%) patient, with a grade 3 pulmonary infection. The median operation time was 332 min (range, 142–470 min), and the median intraoperative blood loss was 150 ml (range, 80–300 ml). The median hospital stay was 12.5 days (range 7-22). There was no perioperative death. Grade 3-4 TRAEs were Neutropenia (9.7%), leukopenia (9.7%), abnormal liver function (6.5%), anemia (6.5%), sensory neuropathy (3.2%), pneumonia (3.2%). Conclusions: Our results preliminarily confirms that Chinese elderly patients with locally advanced ESCC can benefit from neoadjuvant sintilimab combined with chemotherapy, similarly with this combination treatment in all age patients.
Clinical characteristics and survival trends of patients with metastatic colorectal cancer (mCRC) and peritoneal carcinomatosis who receive metastases surgery in a Spanish cohort.
Authors: Marianela Bringas, Javier Soto, Natalia Gutiérrez Alonso, Andrés J. Muñoz Martín, Aitana Calvo Ferrándiz, Gabriela Torres Pérez-Solero, Laura Ortega, Rocío Martín Lozano, Roberto Jiménez Rodríguez, Irene Gonzalez Caraballo, Ana Gutierrez Ortiz de la Tabla, Carlos López Jiménez, David Salomon Juliao Caamaño, María Palma Gómez, Mónica Benavente de Lucas, Marc Ariant Cañete Muñoz, Manuel Alva Bianchi, Íñigo Martínez Delfrade, Miguel Martin, Pilar Garcia-Alfonso
Journal: Journal of Clinical Oncology (2023)

159 Background: Peritoneal metastases in patients with mCRC are commonly associated with poor outcomes. Some of these patients are candidates to undergo metastases surgery, which may result in better prognosis; however, clinical and molecular characteristics of these patients remain uncertain. Methods: We conducted a retrospective analysis of 166 patients with mCRC and peritoneal metastases in a tumor registry from 2015 to 2021, analyzing the clinical and molecular characteristics, as well as progression-free survival (PFS) and overall survival (OS) of patients who received peritoneal surgery versus those who did not. Results: From the whole population, 65 patients (39%) underwent peritoneal metastases surgery, and several characteristics were more frequent in this subgroup: ECOG 0 (n = 26, OR 2.75, p = 0,0069), age &amp;lt;65 years (n = 43, OR 2.29, p = 0,0162), absence of hepatic metastases (n = 56, OR 3.31, p = 0,0037), single metastatic location (n = 43, OR 3.48, p = 0,0002), normal CEA levels at diagnosis (n = 33, OR 2.02, p = 0,0455) and BRAF mutation (n = 12, OR 3.32, p = 0,0345). Moreover, these patients received more lines of systemic treatment (2.8 vs 2, p = 0,006) and more metastases surgeries (1.7 vs 0.9, p = 0,000). Significant differences in tumor mutational status regardless of BRAF (KRAS, NRAS, MSI, PI3K and HER2), sex and primary tumor location between groups were not found. PFS was longer in patients receiving metastases surgery (median, 13.68 vs 7.76 months; HR for progression 0.64; 95 % confidence interval (CI) 0.46 to 0.89; p = 0,009), as well as overall survival (median NR vs 29.53; HR for death 0.39; 95 % CI, 0.25 to 0.60; p = 0,000). Conclusions: In our cohort, patients with mCRC and peritoneal carcinomatosis who underwent metastases surgery had more frequently less than 65 years, ECOG 0, absence of liver metastases, single metastatic location, normal CEA levels at diagnosis and BRAF mutation. Moreover, this subgroup showed better outcomes with a statistically significant increase in PFS and OS.
Effect of early antibiotic exposure on survival of patients receiving atezolizumab plus bevacizumab but not sorafenib for unresectable HCC: A sub-analysis of the phase III IMbrave150 study.
Authors: Claudia A.M. Fulgenzi, Cian Murphy, Antonio D'Alessio, Bernhard Scheiner, Matthias Pinter, Alessio Cortellini, David J. James Pinato
Journal: Journal of Clinical Oncology (2023)

597 Background: The combination of atezolizumab plus bevacizumab (A+B) is the standard of care for patients (pts) with unresectable/advanced hepatocellular carcinoma (HCC). Emerging evidence suggest a detrimental role of early antibiotics (ATB) exposure in immunotherapy recipients. However, it is unclear whether ATB affect outcomes of pts receiving A+B. Methods: We conducted a patient-level analysis of subjects receiving either A+B or Sorafenib (Sor) within the IMbrave150 trial to assess the impact of early ATB exposure (ATB+, i.e. +/-30 from treatment initiation) on overall (OS) and progression-free survival (PFS). Differences in median (m) OS and mPFS were estimated by the Kaplan-Meier method. Cox proportional regression models were used to assess the prognostic impact of ATB+ adjusting for race, age, baseline AFP, baseline ALBI grade, continent of origin and neutrophil-to-lymphocyte ratio, a measure of systemic inflammation. Results: Data of 420 IMbrave150 participants were made available by Vivli. Among them, 278 received A+B and 142 Sor. Most pts were of ECOG performance status 0 (65%); 47% had extrahepatic spread, 40% had macrovascular invasion and 35% had AFP&gt;400 ng/mL. Viral aetiology (39% HBV and 24% HCV) was the most common risk factor for HCC. Overall, 60 pts in the A+B arm (21.5%) and 31 (21.8%) in the Sor group were ATB+. Baseline characteristics were well balanced across ATB groups, except for region of origin, with a higher proportion of Asian pts in ATB+ (60% vs 45%; p=0.01). After a median follow-up of 10.38 months (95%CI:8.6-12.5), OS and PFS rates at 12 months were 72.3% and 9.7% in A+B; 64.8%, and 1.4% in Sor, respectively. ATB+ exposure was associated with increased risk of death both in univariate (HR 1.67; 95%CI 1.04-2.69) and multivariate models (HR 1.62; 95%CI 1.40-1.89) in the A+B (p for interaction &lt;0.001), but not in the Sor arm (univariate HR 0.63; 95%CI 0.32-1.25; multivariate HR 0.70; 95%CI 0.31-1.60). Similarly, the risk of progression was increased for ATB+ pts in the A+B arm (univariate HR 1.68; 95%CI 1.03-2.71; multivariate HR 1.59; 95%CI 1.40-1.81), but not in the Sor arm (univariate HR 0.51;95%CI 0.26-1.01; multivariate HR 0.53; 95%CI 0.21-1.30) with positive p for interaction (p=0.002). Objective response rate (ORR) according to RECIST v.1.1 did not differ between ATB+ (28.0%) and ATB- (30.0%) in A+B (p=0.68). Conclusions: In a post-hoc sub-analysis of IMbrave150 we demonstrate for the first time the negative impact of early antibiotics exposure on outcomes of patients receiving A+B but not in those treated with Sor. Prospective translational studies should evaluate the role of ATB-mediated gut dysbiosis as a proposed mechanism underlying the adverse outcome in immunotherapy-recipients.
The efficacy of immune checkpoint inhibitors in biliary tract cancer with KRAS mutation.
Authors: Sun Young Jeong, Seung Tae Kim, Jae Yeon Jang
Journal: Journal of Clinical Oncology (2023)

598 Background: Biliary tract cancer (BTC) is rare cancer but has a poor prognosis with only 10% of 5-year overall survival (OS). The treatment of advanced BTC remains challenging with limited standard options. With a 15% of incidence, KRAS is one of the most common mutations in BTC. The immune checkpoint inhibitor as salvage therapy has modest activity in BTC. Methods: We conducted molecular profiling including tumor mutational burden in BTC patients with immune checkpoint inhibitors (ICI) as salvage therapy. Programmed death ligand 1 (PD-L1) expression on tumor cells and on tumor-infiltrating lymphocytes (TIL) was also assessed. Results: Between 2020 to 2022, a total of 62 patients were analyzed. The median age was 68 (58.0-73.0). 47 patients (75.8%) received pembrolizumab and 15 (24.2%) received nivolumab as salvage therapy. All patients received gemcitabine plus cisplatin as the frontline therapy, and 53.2% had fluoropyrimidine plus oxaliplatin (FOLFOX) before ICIs. The median lines of prior chemotherapy were 2.5 (2.0-3.0). KRAS mutation was found in 14 patients (22.6%). 28 patients (45.2%) were positive for PD-L1. There was no statistical correlation between KRAS mutation and PD-L1 expression. The median OS and PFS of patients were 5.2 and 3.5 months respectively. There were no statistically significant differences in PFS according to the status of KRAS mutation (Mutant type vs. Wild type) and PD-L1 expression (Positive vs Negative). In subgroup analysis, patients with KRAS mutation and PD-L1 positivity had longer PFS as compared to patients with KRAS mutation and PD-L1 negative (6.5 vs 2.6 months, p=0.047). This finding was not shown in patients without KRAS mutation. Conclusions: The PD-L1 expression might be a novel biomarker for ICIs in BTC patients with KRAS mutation but not in those with the wild type of KRAS.